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669 Background: Premalignant pancreatic cellular genotype may remain stable for many years, but compounding conditions can produce rapid malignant cellular transformation. This onset is rarely spontaneous and is often associated with the presence of inflammation. One inflammatory modulator is “tissue factor (TF),” which usually acts in complex with “coagulation factor VIIa (fVIIa)” to initiate coagulation. The role of TF in malignancy and its impact beyond thrombosis on cell proliferation, angiogenesis, and metastasis is well established. This suggests that TF may be a diagnostic marker in the inflammatory microenvironment of the precursor lesions of pancreatic cancer. Aim: To examine the potential of TF concentrations and the fVII:TF ratio within pancreatic cyst fluid as indicators of malignant cellular transformation from benign to malignant. Methods: Cyst fluid was prospectively collected from 31 patients with pancreatic cystic lesions (REC 18/LO/0736) and analysed in a blinded fashion. The level of TF and fVIIa proteins were measured by ELISA, and the fVIIa:TF ratios calculated. A cut-off value for TF concentration was determined using a ROC curve and compared to the conventional assessment parameters, including radiological features, carcinoembryonic antigen (CEA) and amylase. Results: Patients were categorised into four groups based on histology. Significant histological stage-dependent increases in TF level were observed, which corresponded to the progression of the normal ductal epithelium to invasive adenocarcinoma. The mean TF concentration was significantly higher ( p= 0.006) in the high-risk group (high-grade dysplasia & malignant; 1.17 ng/ml, 95% CI 0.68, 1.67) vs the low-risk group (benign & low-grade dysplasia; 0.27 ng/ml, 95% CI 0.1, 0.44). A strong positive correlation between TF concentration and the high-risk group was observed (correlation coefficient 0.746, p < 0.001, the cut-off value for TF 0.75 ng/ml, AUC 0.877, p= 0.002). In addition, the fVIIa:TF ratio, was marginally lower ( p= 0.274) in the high-risk group (mean = 84.82 [95% CI 0, 185.04]) vs the low-risk group (mean = 437.46 [95% CI 0, 901.02]). TF concentrations performed consistently better as an indicator of malignant transformation when compared to the conventional parameters and will be presented at the meeting. Conclusions: Cyst-associated TF levels appear to correlate with the cytological progression to the malignant phenotype, while the fVIIa:TF ratio indicates a breakdown in the ability of the body to contain the disease. Such indicators may allow better presurgical discrimination of malignant potential of tumours and offer a more nuanced tool for monitoring indeterminate cystic lesions. Further work is needed with a larger cohort to confirm these findings.

638 Background: HA is a major component of the tumor microenvironment (TME) in PDA. PEGPH20 degrades tumor HA, remodeling the TME. In PDA models, PEGPH20 has shown antitumor activity and increased TME delivery of anticancer agents to improve efficacy. A randomized phase 2 study showed promising results for PEGPH20+AG (PAG) in mPDA and identified HA accumulation as a biomarker. We present results from a phase 3 study (NCT02715804) of PAG for pts with HA-high mPDA. Methods: Pts ≥18 years with untreated HA-high mPDA were randomized (stratified by geographic region) 2:1 to PAG or placebo+AG (AG). HA status was prospectively determined with VENTANA HA RxDx Assay, with HA-high defined as ≥50% staining of a tumor sample. Treatment was administered IV in 4-wk cycles (3 wks on, 1 wk off) until progression or intolerable adverse events (AEs): PEGPH20 3.0 µg/kg twice wkly for Cycle 1 and once wkly (QW) thereafter, A 125 mg/m2 QW and G 1000 mg/m2 QW. Prophylactic enoxaparin 1 mg/kg was given daily for thromboembolism (TE) risk. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. Response was independently assessed per RECIST v1.1. The estimated sample size was ~500 pts to detect a hazard ratio (HR) for OS of 0.67 (93% power, 2-sided α = 0.05) after 330 deaths. Results: As of 20 May 2019, 494 pts were randomized with 492 (327 for PAG and 165 for AG) included in ITT analyses (2 pts excluded due to site violations). Baseline characteristics were balanced for PAG vs AG. After 330 deaths, median OS for PAG vs AG was 11.2 vs 11.5 mo (HR 1.00, 95% CI 0.80–1.27; P = 0.97); median PFS was 7.1 vs 7.1 mo (HR 0.97, 95% CI 0.75–1.26); confirmed ORR was 34% vs 27%. Grade (G) 3+ AEs (PAG vs AG) included neutropenia (44% vs 47%), thrombocytopenia (21% vs 16%) and fatigue (16% vs 10%); G3+ rates were 6% vs 7% for TE events, 5% vs 2% for bleeding events and 13% vs 5% for musculoskeletal events. Conclusions: PAG did not improve clinical outcomes vs AG. The PAG safety profile was consistent with that of previous studies. Clinical trial information: NCT02715804.

4003 Background: Level A evidence supports use of CisGem as first-line chemotherapy for ABC; no robust evidence is available for second-line chemotherapy. Methods: Pts diagnosed with ABC with disease progression after prior CisGem were randomised (1:1) to either ASC+mFOLFOX or ASC. Randomisation was stratified by serum albumin levels ( < 35 vs ≥35 g/L), platinum sensitivity (determined from first-line CisGem) and disease extent (locally advanced vs metastatic). Pts with ECOG PS0-1, adequate haematological, renal and liver function, and adequate biliary drainage were eligible. Primary end-point was overall survival (OS) (multivariable Cox regression adjusted for stratification factors); sample size: 162 pts delivering 148 events were required (80% power; 5% two-sided alpha) for a hypothesised hazard ratio (HR) of 0.63. Assumed median survival for ASC was 4 months. Results: 162 pts (81 in each arm) were randomised (27 March ‘14 - 04 Jan ‘18); median age 65 yrs (range 26-84); sex: 80 (49%) male, 82 (51%) female; primary site: intrahepatic 72 (44%), extrahepatic 45 (28%), gallbladder 34 (21%) and ampullary 11 (7%). Baseline characteristics were balanced between arms except platinum sensitivity (ASC+mFOLFOX 27 pts (33%); ASC 34 pts (42%)). After 150 OS events, the adjusted HR was 0.69 (95% CI 0.50-0.97; p = 0.031; ASC+mFOLFOX vs ASC). Median OS (months (m)), 6m and 12m OS-rate (%) were 6.2m, 50.6% and 25.9% for the ASC+mFOLFOX and 5.3m, 35.5%, 11.4% for the ASC arm, respectively. Grade 3/4 toxicities were reported in 48 (59%) and 32 (39%) pts in the ASC+mFOLFOX and ASC arm, respectively; these were balanced between arms except for fatigue and neutropenia (more frequent in ASC+mFOLFOX arm); data cleaning is ongoing. No chemotherapy-related deaths were reported. Conclusion: Survival with ASC was greater than assumed; ASC+mFOLFOX improved OS after progression to CisGem with a clinically meaningful increase in 6m and 12m OS rate. ASC+mFOLFOX should become standard of care in second-line for ABC. Clinical trial information: NCT01926236.

4002 Background: ABCs exhibit increased VEGF expression, correlating with metastatic disease. Combining cediranib (which inhibits VEGFR1, 2 and 3 tyrosine kinase and VEGF-induced signaling in endot...

e15066 Background: The role of palliative radiotherapy (pRT) in patients with metastatic OG cancer remains poorly defined. We report on the outcomes of patients treated with pRT to primary tumor in...

3018 Background: Since publication of the registration trial in 2010 (Hodi et al, NEJM 2010;363:711-23), real world use of ipilimumab (Ipi) in previously treated advanced melanoma patients has extended beyond the specific trial entry criteria of ECOG PS 0-1. We undertook a review of UK patients (pts) treated in the international EAP prior to European licensing of Ipi in August 2011, to compare real world survival outcomes. Methods: UK clinicians registered in the EAP provided anonymised data using pre-specified variable fields for all pts. The EAP stipulated pts should have previously treated, unresectable stage III or IV metastatic melanoma and receive Ipi 3 mg/kg, 3 weekly IV, for up to 4 cycles. Response using RECIST criteria was assessed 12 weekly. Grade ≥3 adverse events (AEs) using CTCAE v3.0 were collected. Results: To date, information on 162 pts has been received from 16 UK sites. Primary sites were: 78% cutaneous, 4% ocular, 1% mucosal, 17% unknown. 78% pts had M1c disease, 14% had brain metastases. No prior therapies ranged from 0-4, 72% pts received 1 prior therapy. Median age was 60 years, men>women (1.6:1). ECOG PS was: 38% 0, 47% 1, 14% 2, 1% 3. BRAF status was known in 38% cases and WT in 75% of these. 19% pts were on steroids at baseline. No cycles delivered was 4 in 52%, 3 in 13%, 2 in 16%, 1 in 17% pts. Most frequent reason for stopping early was clinical evidence of disease progression (71%), death (16%) or unacceptable AE (12%). 32% pts experienced a grade ≥3 AE, the most common being diarrhoea (13%) and fatigue (8%). Complete and partial responses were reported in 1% and 21% of treated pts. At median follow-up of 17 months, median progression free survival and overall survival (OS) were 2.8 and 5.7 months, 1 year OS was 30%. Comparing outcomes of various pt subgroups, the strongest prognostic factor for OS was ECOG PS at the start of treatment (p

e15116 Background: Osteonecrosis of the jaw (ONJ) occurs in 1-10% of cancer patients treated with intravenous bisphosphonates. Mean time of exposure to zoledronic acid (ZA) prior to the event has b...

15047 Background: Reported incidence of Ox hypersensitivity is 12–16%(Brandi G et al. Hypersensitivity reactions to oxaliplatin. Br J Cancer 2003; 89:477–81.). Ox is one of the most active agents i...

4583 Background: Randomised phase III studies in APC, reveal that many patients (pts) (∼20–25%) die within 3 months from randomisation [(Early Death Burden) (EDB)]. More compared to studies done in other cancers despite pts entered on similar ‘global’ clinical criteria (e.g. 7% in colorectal cancer). We hypothesised that EDB in APC is related to hyper-coagulability. Prevention of veno-thromboembolism (VTE) may result in reduction of EDB. To test this we initiated the randomised phase IIb FRAGEM study. Methods: Upon written informed consent pts with inoperable APC, are eligible for the study (MREC N° 07/02/129, UKCRN 1290). Concurrent VTE or anticoagulant therapy are exclusion criteria. Standard arm pts (arm A) receive gemcitabine 1gr/m2 weekly (Burris schedule). Arm B also receives daily dalteparin injections for 12 weeks at therapeutic dose (CLOT schedule). Primary end point is the reduction of VTE, secondary endpoint the reduction of EDB. To detect a reduction of VTE from around 25% to 5% (odds ratio of 0.158), using a two-group chi-squared test with a two-sided 5% significance level and 80% power, a minimum of 59 pts per treatment group are required. Interim analysis was planned after the first 25 pts entered into arm B to exclude toxicity from dalteparin’s therapeutic, given prophylactically, dose. These results are presented here. Results: 26 pts (50% male, 61% with metastases) in arm A and 25 pts (60% male, 44% with metastases) in arm B have been treated so far. The incidence of VTE in arm A was 31% with 3 pts developing leg deep vein thrombosis (DVT) with pulmonary embolism (PE), 2pts DVT, 1 pt splanchnic vein thrombosis and PE, 1 pt PE without DVT and 1 patient a stroke. No VTE observed in arm B. Haemorrhagic events were 7.5% and 4% in arm A and B respectively. Within the first 12 weeks period 4 pts (15%) in arm A died, 2 from PE (autopsy- confirmed in one ‘sudden death’), 1 from stroke and one from progressive cancer. The VTE related mortality was 37%. In arm B the EDB was 4% as 1 pt died from sepsis. Conclusions: Results of the interim analysis indicate that the dose of dalteparin is safe. They also support our hypothesis that reduction of VTE may result in reduction of the EDB. The trial is on course to achieve its primary endpoint. No significant financial relationships to disclose.

4213 Introduction: Gemcitabine is currently the standard treatment for patients (pts) with unresectable pancreatic cancer. It is beneficial but not associated with a high response rate. Retinoids are derivatives of vitamin A that have numerous effects on tumour cells, including inhibition of cell growth, and induction of differentiation and apoptosis. The effects of retinoic acid (RA):9-cis-RA or all-trans-RA (ATRA) on pancreatic tumour cell lines include inhibition of in vitro and in vivo growth, accompanied by differentiation, apoptosis, or both. Some studies evaluating combinations of RA and chemotherapeutic agents such as cisplatin, etoposide and paclitaxel have demonstrated synergy. Our data showed that pretreatment of pancreatic cell lines with RA followed by gemcitabine resulted in a dramatic increase in apoptosis. We therefore conducted a phase II pilot study of gemcitabine in combination with 13-cis RA in pts with locally advanced or metastatic carcinoma of pancreas. Methods: Study treatment was:...

1570 Background: Conventional treatment for patients with brain metastases is whole-brain radiotherapy (WBRT). Efficacy is poor and median survival for these patients is 2–3 months. One way to incr...